Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice
Maria I. Bergamasco, … , Tim Thomas, Anne K. Voss
Maria I. Bergamasco, … , Tim Thomas, Anne K. Voss
Published April 1, 2024
Citation Information: J Clin Invest. 2024;134(7):e167672. https://doi.org/10.1172/JCI167672.
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Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice

Abstract

Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/–), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/– mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/– mice and partially reversed gene expression changes in Kat6b+/– cortical neurons. Both compounds improved sociability in Kat6b+/– mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.

Authors

Maria I. Bergamasco, Hannah K. Vanyai, Alexandra L. Garnham, Niall D. Geoghegan, Adam P. Vogel, Samantha Eccles, Kelly L. Rogers, Gordon K. Smyth, Marnie E. Blewitt, Anthony J. Hannan, Tim Thomas, Anne K. Voss

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Figure 1

mRNA, H3K9ac, and H3K23ac levels and mitochondrial function in HEK293T cells carrying SBBYSS-specific KAT6B mutations.

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mRNA, H3K9ac, and H3K23ac levels and mitochondrial function in HEK293T c...
(A) Diagram of SBBYSS mutations analyzed. Colors indicate protein-coding domains; boxes indicate individual KAT6B exons. Gray, 5′ UTR; purple, conserved N-terminal domain; orange, tandem PHD fingers; blue, MYST histone acetyltransferase domain; red, acidic region; green and yellow, serine- and methionine-rich regions. (B) KAT6B mRNA levels normalized to GAPDH in control and HEK293T cells carrying SBBYSS-causing mutation assessed by quantitative reverse-transcriptase PCR (qRT-PCR). (C and D) Quantitation of H3K9ac (C) or H3K23ac (D) levels normalized to pan H3 in HEK293T cells carrying SBBYSS-causing mutations assessed on Western blots shown in Supplemental Figures 1 and 2. (E) Representative maximal projection confocal microscopy images of control and HEK293T cells carrying SBBYSS-causing mutations stained with MitoTracker. Scale bar: 10 μm. (F) ATP levels assessed by Mitochondrial ToxGlo assay in control and HEK293T cells carrying SBBYSS-causing mutations normalized to controls. n = 3–5 individual clonal HEK293T cell lines per SBBYSS mutation. Data are represented as mean ± SEM and were analyzed by 1-way ANOVA with Holm-Šidák correction for multiple testing (B–D and F). P values for each mutation are shown above each bar. Circles, individual clonal cell lines. Related data in Supplemental Figures 1–4.